Is AKT2 p.Arg274= (c.822C>T) pathogenic?

AKT2 p.Arg274= (c.822C>T) is classified Likely benign in AKT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). Very rare (popmax 0.00659%, sas); Associated with type 2 diabetes mellitus.

What condition is associated with AKT2 p.Arg274= (c.822C>T)?

AKT2 p.Arg274= (c.822C>T) is associated with type 2 diabetes mellitus, hypoinsulinemic hypoglycemia and body hemihypertrophy (ClinVar).

How common is AKT2 p.Arg274= (c.822C>T) in the general population?

AKT2 p.Arg274= (c.822C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

AKT2 p.Arg274=

c.822C>T · rs758906645 · VCV1548180

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -4.5
Overall
CADD	0.044	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,030 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00174% 28/1,613,562 alleles · very rare exomes 25/1,461,350 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,172
European (non-Finnish)	0.0017%	58,996
Admixed American	0.00167%	59,966
Remaining individualsnot grpmax-eligible	0.0016%	62,474

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AKT2
Protein: p.Arg274=
Coding: c.822C>T
MANE Select: NM_001626
dbSNP: rs758906645
Type: single nucleotide variant
Location: chr19:40237978 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 82.79 · 19 PDB
Residue 274: the protein kinase domain; a UniProt-annotated variant site (risk factor for t2d; typical metabolic dyslipidemia with elevated fastin triglyceride, high vldl triglyceride/cholesterol ratios, low hdl cholesterol levels and high small dense ldl levels; de novo lipogenesis and liver fat are also significantly elevated)

Full AKT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypoinsulinemic hypoglycemia and body hemihypertrophy

Similar variants

AKT2 p.Arg274His Likely pathogenic ★ same residue
AKT2 c.709-3C>G Uncertain significance ★★ same condition
AKT2 c.960+3G>T Uncertain significance ★★ same condition
AKT2 p.Ala214Val Uncertain significance ★★ ⚠ same condition
AKT2 p.Arg113Trp Uncertain significance ★★ ⚠ same condition
AKT2 p.Arg15His Uncertain significance ★★ ⚠ same condition
AKT2 p.Arg253Gln Uncertain significance ★★ ⚠ same condition
AKT2 p.Arg347Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/akt2-p-arg274 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown